Several types of polyomavirus gain cell entry by recognizing a sialic acid-containing component on the cell surface for initial attachment and subsequent association with the cells.
BK polyomavirus (BKV or BKPyV) is latent in most individuals of the general population. However, late onset haemorrhagic cystitis, BKV nephropathy, and ureteral stenosis are all associated with BKV reactivation, for example, in immunosuppressed individuals. Lytic infection resulting from reactivation is most commonly noted in renal and bone marrow transplant patients, respectively (S. D. Gardner et al. (1971) Lancet 1253; L. K. Dropulic et al. (2008) Bone Marrow Transplant. 41: 11-18.) Two forms of the virus, archetype virus and rearranged variants, exist and are identified based on the DNA sequence structure of the non-coding control region. Archetype virus can be commonly isolated from the urine of both healthy individuals, as a result of transient reactivation events, as well as patients with disease (M. J. Imperiale, et al (Eds.). (2007) Fields Virology, Lippincott Williams & Wilkins, pp. 2263-2298; K. Doerries et al. (2006) Adv. Exp. Med. Biol. 577: 102-116.). In contrast, rearranged variants are most often found in the serum of patients with BKPyV-associated diseases.
BKPyV infection can occur through a host of different cell types and tissue throughout the body, however the main site of BKPyV reactivation and replication is within the kidneys and urinary tract. The virus is able to reactivate in renal transplant and bone marrow transplant patients, furthermore, BKPyV reactivation and disease, albeit rarely, have been observed in other immunocompromised conditions including systemic lupus erythematosus noted in other solid organ transplant recipients, in patients with HIV/AIDS (M. Jiang et al. (2009) Virology 384:266-273), fatal pneumonia, native kidney nephritis and encephalitis (A. Galan et al. (2005) Hum. Pathol. 36:1031-1034; E. S. Sandler et al. (1997) Bone Marrow Transplant. 20: 163-165; 0. Cubukcu-Dimopulo et al. (2000) Am. J. Surg. Pathol. 24: 145-149.)
A non-enveloped virus, BKPyV is comprised of essentially a protein capsid and DNA. It consists mainly of the building blocks that serve as the structure of the viral capsid: VP1, VP2 and VP3. The capsid surrounds the double-stranded circular DNA genome integrated with histones. BKPyV infection is noted in cells with cell surface gangliosides.
Currently, treatment of polyomavirus-associated nephropathy consists of reducing immunosuppression in the transplant patients. Additionally, other known drug therapies for infections of DNA viruses have been tested for efficacy towards BKPyV infections including cidovir, leflunomide, and fluoroquinolones (S. Safrin et al. (1997) Rev. Med. Virol. 7:145-156; M. A. Josephson et al. (2006) Transplantation 81: 704-710. S. Gabardi, S. S. et al. (2010) Clin. J. Am. Soc. Nephroi. 5: 1298-1304.)
JC polyomavirus infection is species specific and only noted in humans. The cellular receptors recognized by JC virus include the N-linked glycoprotein with an alpha (2,6)-linked sialic acid 12 present on many human cells and the serotoninergic 5HT2a receptor in permissive astroglial cell cultures (Komagome R et al. (2002) J Virol. 76:12992-3000). 5HT2a is present in several tissue, including the kidney, on epithelial cells, in the blood on B lymphocytes and platelets, and in the CNS on glial cells and neurons (Gray J A et al. (2001) Mol Pharmacol. 60:1020-30; Fonseca M I et al. (2001) Brain Res Mol Brain Res. 89:11-9). JCV infection has a narrow host cell range; JCV DNA has been detected in oligodendrocytes, astrocytes, lymphocytes, kidney epithelium cells, tonsil stromal cells, and plasma cells (Monaco M C et al. (1998) J Virol. 72:9918-23; Tan, C S et al. (2009) J Infect Dis.). JCV pathogenesis largely occurs in immunocompromised settings and leads to a number of CNS pathologies including progressive multifocal leukoencephalopathy (PML), granule cell neuronopathy (GCN), encephalopathy and meningitis (Tan, C et al. (2011) Lancet Neurol. 9: 425-437).
PML is a demyelinating disease of the CNS caused by the reactivation of the human JC polyomavirus (JCV or JC PyV). Often fatal, PML is a consequence of a productive JCV infection of oligodendrocytes and to a lesser extent, astrocytes some of which harbor late JCV genes and are destroyed, while others withstand a failed infection and appear transformed. Symptoms vary and include weakness, sensory deficit, hemianopsia, cognitive dysfunction, aphasia, or coordination and gait difficulties. Alternatively, GCN arises from JC infection and subsequent destruction of granule cell neurons in the cerebellum (Koralnik I J et al. (2005) Ann Neurol. 57:576-80.). GCN patients present with subacute or chronic onset of cerebellar dysfunction, including gait ataxia, dysarthria and incoordination, and show cerebellar atrophy upon MRI analysis.
The JC virus is a polyomavirus which harbors a circular enclosed double stranded DNA from which the genes responsible for viral transformation, gene regulation, and replication are encoded counterclockwise and the non-coding regulatory region and the late genes for the agnoprotein and the viral capsid proteins, are encoded clockwise. The coding region consists of 90% of the viral sequence. Following primary infection, JCV can remain dormant in the kidneys, bone marrow and lymphoid tissue (Monaco M C et al. (1996) J Virol. 70:7004-12; Tan C S et al. (2009) J Infect Dis. 199:881-8; Randhawa P et al. (2005) J Infect Dis. 192:504-9).
JCV infection is mainly diagnosed in immunocompromised patients. PML is a fatal disease and although there is no specific treatment, immunocompromised patients i.e., HIV patients, susceptible to JCV are noted to have a better prognosis with the advent of combination antiretroviral therapy. Monoclonal antibody therapies for autoimmune disorders, including natalizumab for multiple sclerosis, efalizumab for psoriasis and rituximab for non-Hodgkin lymphoma, have also been associated with the onset of PML resulting from JCV infection due to their suppression of the immune system (FDA MedWatch: US Dept of Health and Human Services. 2009; Schwab N et al. (2009) Multiple Sclerosis 15:S271-S7).